Project 1 will focus on the biology of synuclein in human brain and on the contributions of synuclein-associated abnormalities (i.e. Lewy bodies and Lewy-neurites) to the cognitive impairments that occur in PD. Two observations link alpha-synuclein to PD: mutations in the alpha-synuclein gene cause autosomal dominant PD and alpha-synuclein accumulates in Lewy bodies and Lewy neurites, pathological hallmarks of PD. However, details on the distribution and expression of alpha, beta-, and gamma-synucleins in the brain of normal humans and cases of PD are not known. In Specific Aim 1, we propose to conduct detained studies of the localization and expression of alpha-, beta-, and gamma-synucleins in brain from cases of PD and controls using RT-PCR, immunoblots and immunocytochemistry. In Specific Aim 2, we will examine the pathological substrates of cognitive impairments in PD, focusing on synuclein-associated abnormalities (LB and Lewy neurites) in cortical and subcortical structures; loss of neurons in pathological correlations will be complemented by measurements of levels of synuclein, synaptophysin, and neurotransmitter markers in cortical and subcortical structures relevant to cognitive impairments. Although a large body of evidence has implicated oxidative stress in the pathogenesis of PD, little is known about the accumulation of oxidative damage to specific proteins, i.e. synuclein, neurofilaments, and other proteins relevant to PD ( TH, VMAT2, DAT). In Specific Aim 4 we will examine levels of oxidative damage of specific proteins in PD.